U.S. patent number 8,143,400 [Application Number 12/007,394] was granted by the patent office on 2012-03-27 for process for the preparation and purification of cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidine hydrochloride.
This patent grant is currently assigned to Apotex Pharmachem Inc.. Invention is credited to Elena Bejan, Svetoslav S. Bratovanov, Stephen E. Horne, Abbulu Kante, David A. Stradiotto, Zhi-Xian Wang.
United States Patent |
8,143,400 |
Bratovanov , et al. |
March 27, 2012 |
Process for the preparation and purification of
cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidine
hydrochloride
Abstract
An industrially acceptable process for the preparation and
purification of cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidine
from a cis/trans mixture of isomers. Treatment of the mixture with
an organic sulfonic acid generates a less soluble acid addition
salt that is enriched in the cis-isomer. Recrystallization or
pulping using various organic solvents allows for enrichment of the
cis-isomer by filtration. These new sulfonic acid salts of the
cis-isomer of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine
prepared according to the present invention could be further
converted into the hydrochloride salt by any known procedures such
as treatment with a base and then hydrochloric acid salt formation
or exchange of the sulfonic acid salt with hydrochloric acid.
Inventors: |
Bratovanov; Svetoslav S.
(Ancaster, CA), Bejan; Elena (Brantford,
CA), Stradiotto; David A. (Brantford, CA),
Kante; Abbulu (Brantford, CA), Wang; Zhi-Xian
(Tianjin, CN), Horne; Stephen E. (Burlington,
CA) |
Assignee: |
Apotex Pharmachem Inc.
(Brantford, CA)
|
Family
ID: |
40851240 |
Appl.
No.: |
12/007,394 |
Filed: |
January 10, 2008 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20090182146 A1 |
Jul 16, 2009 |
|
Current U.S.
Class: |
546/18;
546/19 |
Current CPC
Class: |
C07D
497/20 (20130101) |
Current International
Class: |
C07D
401/14 (20060101) |
Field of
Search: |
;546/18,19 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Saunders, et al., "Synthesis and characterization of all four
isomers of the muscarinic agonist . . . ", J. Med. Chem., (1987),
vol. 30, 969-975. cited by other.
|
Primary Examiner: Anderson; Rebecca
Claims
The invention claimed is:
1. A process for the preparation and purification of the cis-isomer
of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine hydrochloride
comprising: (a) treatment of a cis/trans mixture of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidine with an organic
sulfonic acid in an organic solvent or a mixture thereof; (b)
purification of the mixture obtained at step (a) by
recrystallization or pulping in an organic solvent or a mixture
thereof; (c) hydrochloric acid salt formation by treatment of the
salt obtained at step (b) with hydrochloric acid or treatment with
a base and then hydrochloric acid.
2. The process of claim 1 wherein the reaction of cis/trans mixture
of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine at step (a) is
performed using methanesulfonic acid, racemic or optically active
camphorsulfonic acid, benzenesulfonic acid or p-toluenesulfonic
acid.
3. The process of claim 1 wherein the reaction of cis/trans mixture
of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine at step (a) is
performed using racemic or optically active camphorsulfonic
acid.
4. The process of claim 1 wherein the reaction of cis/trans mixture
of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine at step (a) is
performed using racemic camphorsulfonic acid.
5. The process of claim 1 wherein the reaction of cis/trans mixture
of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine with an organic
sulfonic acid at step (a) is performed in a solvent selected from
the group consisting of: C.sub.6 to C.sub.9 aryl, a C.sub.7 to
C.sub.10 aralkyl, C.sub.3 to C.sub.6 alkyl ketones, C.sub.4 to
C.sub.8 alkyl ethers, C.sub.1 to C.sub.6 alkyl alcohols and a
mixture thereof.
6. The process of claim 1 wherein the reaction of cis/trans mixture
of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine with an organic
sulfonic acid at step (a) is performed in toluene, acetone, methyl
ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ether,
methanol and butanol or a mixture thereof.
7. The process of claim 1 wherein the reaction of cis/trans mixture
of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine with an organic
sulfonic acid at step (a) is performed in toluene.
8. The process of claim 1 wherein the reaction of cis/trans mixture
of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine with an organic
sulfonic acid at step (a) is performed in a mixture of toluene and
methanol.
9. The process of claim 1 wherein the reaction of cis/trans mixture
of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine at step (a) is
performed using racemic or optically active camphorsulfonic acid in
toluene.
10. The process of claim 1 wherein the reaction of cis/trans
mixture of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine at step
(a) is performed using racemic or optically active camphorsulfonic
acid in a mixture of toluene and methanol.
11. The process of claim 1 wherein the purification of cis/trans
mixture of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine obtained
at step (a) is performed by recrystallization in an organic solvent
or a mixture thereof.
12. The process of claim 1 wherein the purification of cis/trans
mixture of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine obtained
at step (a) is performed by recrystallization in an organic solvent
selected from the group consisting of: C.sub.5 to C.sub.9 alkyl,
C.sub.6 to C.sub.9 aryl, C.sub.7 to C.sub.10 aralkyl, C.sub.4 to
C.sub.10 alkyl ester, C.sub.3 to C.sub.6 alkyl ketones, C.sub.4 to
C.sub.8 alkyl ethers, C.sub.1 to C.sub.6 alkyl alcohols, C.sub.1 to
C.sub.3 carboxylic acids, polyethylene glycols having an average
molecular weight of 300-500, and a mixture thereof.
13. The process of claim 1 wherein the purification of cis/trans
mixture of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine obtained
at step (a) is performed by recrystallization in toluene, methyl
ethyl ketone, methyl isobutyl ketone, methanol, iso-propanol or a
mixture thereof.
14. The process of claim 1 wherein the purification of cis/trans
mixture of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine obtained
at step (a) is performed by recrystallization in toluene.
15. The process of claim 1 wherein the purification of cis/trans
mixture of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine obtained
at step (a) is performed by recrystallization in a mixture of
toluene and methanol.
16. The process of claim 1 wherein the purification of cis/trans
mixture of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine obtained
at step (a) is performed by pulping in an organic solvent or a
mixture thereof.
17. The process of claim 1 wherein the purification of cis/trans
mixture of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine obtained
at step (a) is performed by pulping in organic solvents selected
from the group consisting of: C.sub.5 to C.sub.9 alkyl, C.sub.6 to
C.sub.9 aryl, C.sub.7 to C.sub.10 aralkyl, C.sub.4 to C.sub.10
alkyl ester, C.sub.3 to C.sub.6 alkyl ketones, C.sub.4 to C.sub.8
alkyl ethers, C.sub.1 to C.sub.6 alkyl alcohols, C.sub.1 to C.sub.3
carboxylic acids, polyethylene glycols having an average molecular
weight of 300-500, and a mixture thereof.
18. The process of claim 1 wherein the purification of cis/trans
mixture of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine obtained
at step (a) is performed by pulping in toluene, methyl ethyl
ketone, methyl isobutyl ketone, methanol, iso-propanol or a mixture
thereof.
19. The process of claim 1 wherein the purification of cis/trans
mixture of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine obtained
at step (a) is performed by pulping in toluene.
20. The process of claim 1 wherein the purification of cis/trans
mixture of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine obtained
at step (a) is performed by pulping in a mixture of toluene and
methanol.
Description
FIELD OF THE INVENTION
Novel and industrially acceptable processes for the preparation and
purification of cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidine
from a cis/trans-mixture of isomers are described. The
hydrochloride salt of the cis-isomer of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidine is the active
ingredient in Cevimeline Hydrochloride.
BACKGROUND OF THE INVENTION
The present invention refers to a novel, industrially acceptable
processes for the preparation and purification of
cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidine, from a
cis/trans-mixture of isomers. The hydrochloride salt of the
cis-isomer of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine is
the active ingredient in Cevimeline hydrochloride. This
pharmaceutical is useful for the treatment of diseases of the
central nervous system due to disturbances of central cholinergic
function and autoimmune system (Sjorgen's syndrome) and is marketed
as Evoxac.RTM.
U.S. Pat. No. 4,855,290 teaches a process for the preparation of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidine, wherein the
cis-isomer is isolated via fractional recrystallization of its
hydrochloric salt. A major disadvantage of this method is the use
of repeated (up to 6 times) recrystallizations of the hydrochloride
salt of a cis/trans-mixture of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidine. This procedure
results in an enriched mother liquor in the cis-isomer that by
subsequent chromatographic purification, again undesirable in
industrial settings, results in the isolation of the cis-isomer in
less than 10% yield. Another drawback of the above procedure is the
use of the moisture sensitive and highly reactive boron trifluoride
etherate. This reagent is not easy to handle and as such, requires
special operations to prevent corroding of the reactors. Also, it
should be pointed out that U.S. Pat. No. 4,855,290 uses
dichloromethane, an environmentally unfriendly solvent.
U.S. Pat. No. 4,981,858 describes a process for the resolution of
the enantiomers of the cis and trans diastereomers of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidine. For example, a
racemic sample of the cis or trans diastereomer of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidine is heated with
L-tartaric acid in absolute ethanol, followed by fractional
recrystallization of the dextrorotatory enantiomer from ethanol.
Treatment of the mother liquor with D-tartaric acid allows for
isolation of the levorotatory enantiomer. This patent though does
not teach any industrially acceptable processes for the preparation
and purification of the cis-isomer of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidine.
U.S. Pat. Nos. 5,571,918 and 4,861,886 describe the isomerization
of trans-2-methylspiro(1,3-oxathiolane-5,3')quiniclidine to the
cis-form in the presence of various acids such as tin
tetrachloride. Like boron trifluoride, tin tetrachloride is a very
toxic and moisture sensitive chemical, which makes it a hazardous
and industrially unfriendly choice, especially when transiting to
commercial scale. Also, in terms of delivering pharmaceutical-grade
quality Cevimeline hydrochloride (i.e., >99.5% of the
cis-isomer), we found that these procedures were either inadequate
or too hazardous to be practical.
The lack of industrially advantageous processes for the preparation
of the cis-isomer of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidine prompted us to
search for novel and industrially acceptable processes for the
preparation and purification of the cis-isomer.
Further and other objects of the invention will be realized by
those skilled in the art from the following Summary of the
Invention and Detailed Description of Preferred Embodiments of the
Invention thereof.
SUMMARY OF THE INVENTION
The present invention provides novel processes for the preparation
and purification of the cis-isomer of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidine from a
cis/trans-mixture of isomers. It was discovered that the cis-isomer
of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine, starting from a
cis/trans-mixture (10:1 to 2:1), is selectively converted to a less
soluble organic sulfonic acid salt thereby allowing substantial
enrichment of the cis-isomer by filtration. Adding to the
importance of the above mentioned is the discovery of further
purification by recrystallization or pulping using various solvents
or a mixture thereof allowing the isolation of
pharmaceutically-acceptable
cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidine.
These new sulfonic acid salts of the cis-isomer of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidine prepared according
to the present invention could be further converted into the
hydrochloride salt by any known procedures such as treatment with a
base and then hydrochloric acid salt formation or exchange of the
sulfonic acid salt with hydrochloric acid.
According to one embodiment of the present invention there is
provided a new process for the preparation and purification of the
hydrochloride salt of the cis-isomer of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidine which represents
the active ingredient in Cevimeline Hydrochloride. This process is
robust and easily scalable to industrial levels.
Other advantages of the present invention include the cost
efficiency and simplicity of the process. As well, the Cevimeline
hydrochloride produced meets specifications of >99.5%
cis-isomer. Further, the Cevimeline hydrochloride is produced with
pharmaceutically acceptable residual levels of toluene and organic
sulfonic acid and salts thereof, most preferably the
camphorsulfonic acid and salts thereof. Pharmaceutically acceptable
residual levels for toluene and camphorsulfonic acid and salts
thereof vary for specific jurisdictions and would be known by
persons skilled in the art.
Further and other advantages of this invention will be appreciated
by those skilled in the art.
DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION
According to one aspect of the invention, a novel process is
provided for the preparation and purification of
cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidine from a
cis/trans-mixture of isomers. The process is industrially
practical, efficient, safe and economical as well as
environmentally friendly.
In a preferred embodiment of the invention a cis/trans-mixture of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidine in a cis/trans
ratios from 2:1 to 10:1 is dissolved in organic solvent. Examples
of suitable organic solvents include C6 to C9 aryl, a C7 to C10
aralkyl, C3 to C6 alkyl ketones, C4 to C8 alkyl ethers, C1 to C6
alkyl alcohols or a mixture thereof. Examples of preferred solvents
include toluene, acetone, methyl ethyl ketone, methyl isobutyl
ketone, methyl tert-butyl ether, methanol and butanol or a mixture
thereof. Most preferably the solvent is toluene or mixture of
toluene and methanol (for instance 0.1-3 equiv. of methanol in
toluene). A suitable amount of organic sulfonic acid, preferably
0.5 to 2 equivalents relative to the cis-isomer, is added to the
mixture at temperatures between 0.degree. and 50.degree. C. Most
preferably the acid is methanesulfonic acid, racemic or optically
active camphorsulfonic acid, benzenesulfonic acid or
para-toluenesulfonic acid. The mixture is stirred for 2 to 48 hours
and the precipitate formed is isolated by filtration. The
precipitate contains up to 98% of the cis-isomer of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidine as a sulfonic acid
salt. Additional purification of the salt by recrystallization or
pulping in organic solvents or a mixture thereof at various
temperatures allows reaching the high purity levels required for
use as an active pharmaceutical. Examples of suitable organic
solvents include C5 to C9 alkyl, C6 to C9 aryl, C7 to C10 aralkyl,
C4 to C10 alkyl ester, C3 to C6 alkyl ketones, C4 to C8 alkyl
ethers, C1 to C6 alkyl alcohols, C1 to C3 carboxylic acids,
polyethylene glycols having an average molecular weight of 300-500,
or a mixture thereof. Most preferably the solvent is toluene,
methyl ethyl ketone, methyl isobutyl ketone, iso-propanol,
methanol, acetic acids or a mixture thereof. Examples of suitable
organic solvents include mixtures of toluene and methanol, acetic
acid or polyethylene glycol 400.
The sulfonic acid salts of the cis-isomer of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidine prepared according
to the present invention are further converted into the
hydrochloride salt by any known procedures such as treatment with a
base and then hydrochloric acid salt formation or exchange of the
sulfonic acid salt with hydrochloric acid. The hydrochloride salt
of the cis-isomer of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidine is the active
ingredient in Cevimeline hydrochloride.
The Cevimeline hydrochloride produced according to the present
invention meets specifications of >99.5% cis-isomer.
Example I
Preparation of the
cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin camphorsulfonic
acid salt in toluene
To a mixture of
cis-/trans-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin (5000 mg,
25.1 mmol) containing 70% of the cis-isomer in toluene (25 mL) was
added racemic camphorsulfonic acid (3970 mg, 17.09 mmol) and the
mixture was stirred for 2 hours at room temperature. The thick
precipitate was filtered and the cake washed with toluene to give a
95:5 cis/trans mixture of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidin camphorsulfonic acid
salt (6220 mg, 14.4 mmol). .sup.1H NMR (400 MHz, CDCl.sub.3,
cis-isomer): .delta.=5.16 (q, J=5.9 Hz, 1H); 3.57-3.41 (m, 4H);
3.39-3.30 (m, 2H); 3.27 (d, J=11.2 Hz, 1H); 3.22 (d, J=14.4 Hz,
1H); 3.03 (d, J=11.2 Hz, 1H); 2.83 (d, J=14.4, 1H); 2.61-2.53 (m,
1H); 2.41-2.39 (m, 1H); 2.34-2.27 (m, 1H); 2.21-2.13 (m, 4H);
2.06-1.78 (m, 3H); 1.57 (d, J=5.7 Hz, 3H); 1.42-1.36 (m, 1H); 1.05
(s, 3H); 0.83 (s, 3H).
Example II
Preparation of the
cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin camphorsulfonic
acid salt in toluene
To a mixture of
cis-/trans-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin (2400 mg,
12.1 mmol) containing 71% of the cis-isomer in toluene (25 mL) was
added 1-(S)-camphorsulfonic acid (1960 mg, 8.44 mmol) and the
mixture was stirred for 18 hours at room temperature. The
precipitate was filtered and the cake washed with toluene to give a
96:4 cis/trans mixture of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidin camphorsulfonic acid
salt (1500 mg, 3.4 mmol).
Example III
Preparation of the
cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin camphorsulfonic
acid salt in toluene/methanol
To a mixture of
cis/trans-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin (23.16 g,
116.38 mmol) containing 77% of the cis-isomer in toluene (250 mL)
was added racemic 1-camphorsulfonic acid (20.30 g, 87.20 mmol)
followed by methanol (4.70 mL, 116.38 mmol) and the mixture was
stirred for 18 hours at room temperature. The precipitate was
filtered and the cake washed with toluene to give a 95:5 cis/trans
mixture of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidin
camphorsulfonic acid salt (37.56 g, 87.14 mmol).
Example IV
Preparation of the
cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin methanesulfonic
acid salt in acetone
To a mixture of
cis/trans-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin (5000 mg,
25.1 mmol) containing 70% of the cis-isomer in acetone (25 mL) was
added methanesulfonic acid (1642 mg, 17.09 mmol) and the mixture
was stirred for 2 hours at room temperature. The thick precipitate
was filtered and the cake washed with acetone to give a 89:11
cis/trans mixture of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidin
methanesulfonic acid salt (4000 mg, 13.6 mmol). .sup.1H NMR (400
MHz, CDCl.sub.3, cis-isomer): .delta.=5.16 (q, J=5.9 Hz, 1H);
3.77-3.41 (m, 4H); 3.34-3.25 (m, 3H); 3.06 (d, J=11.3 Hz, 1H); 2.76
(s, 3H); 2.41-2.40 (m, 1H); 2.22-2.16 (m, 2H); 2.14-1.96 (m, 1H);
1.57 (d, J=5.7 Hz, 3H).
Example V
Preparation of the
cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin benzenesulfonic
acid salt in acetone
To a mixture of
cis/trans-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin (500 mg,
2.5 mmol) containing 75% of the cis-isomer in acetone (2.5 mL) was
added benzenesulfonic acid (280 mg, 1.7 mmol) and the mixture was
stirred for 36 hours at room temperature. The precipitate was
filtered and the cake washed with acetone to give a 90:10 cis/trans
mixture of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidin
benzenesulfonic acid salt (400 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3, cis-isomer): .delta.=7.88-7.84 (m, 2H); 7.41-7.36 (m,
3H); 5.11 (q, J=5.6 Hz, 1H); 2.33-2.28 (m, 1H); 1.99-1.86 (m, 2H);
1.83-1.69 (m, 1H); 1.53 (d, J=5.6 Hz, 3H).
Example VI
Preparation of the
cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin methanesulfonic
acid salt in butanol
To a mixture of
cis/trans-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin (500 mg,
2.5 mmol) containing 70% of the cis-isomer in butanol (2.5 mL) was
added methanesulfonic acid (280 mg, 1.7 mmol) and the mixture was
stirred for 24 hours at room temperature. Methyl tert-butyl ether
(6 mL) was added and the mixture was stirred for 2 hours. The
precipitate was filtered and the cake washed with methyl tert-butyl
ether to give a 95:5 cis/trans mixture of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidin benzenesulfonic acid
salt (300 mg, 1.0 mmol).
Example VII
Recrystallization of the
cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin camphorsulfonic
acid salt in toluene
Cis/trans-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin camphor
sulfonic acid salt (1480 mg) containing 96% of the cis-isomer in
toluene (15 mL) was heated to 90-95.degree. C. for 30 minutes. The
heating was stopped and the reaction mixture stirred for 1 hour at
room temperature. The precipitate was filtered and the cake washed
with toluene to give a 98:2 cis/trans mixture of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidin camphor sulfonic
acid salt (1030 mg).
Example VII
Recrystallization of the
cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin camphorsulfonic
acid salt in toluene/methanol
Cis/trans-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin camphor
sulfonic acid salt (70.0 g) containing 94.6% of the cis-isomer in
toluene (350 mL) was heated to 85-90.degree. C. for 30 minutes to
complete dissolution. The heating was stopped and methanol (9.72
mL, 0.24 mol, 1.5 equiv.) was added. The reaction mixture was
allowed to cool to room temperature and stirred for 3-4 hours. The
precipitate was filtered and the cake washed with toluene to give a
98.65:1.35 cis/trans mixture of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidin camphor sulfonic
acid salt (51.45 g). This material was suspended in toluene (257
mL) and heated to 85-90.degree. C. to complete dissolution. The
heating was stopped and methanol (7.3 mL, 1.5 equiv.) was added.
The reaction mixture was allowed to cool to room temperature and
stirred for 3-4 hours. The precipitate was filtered and the cake
washed with toluene to give a 99.64:0.36 cis/trans mixture of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidin camphor sulfonic
acid salt (47.62 g).
Example IX
Recrystallization of the
cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin camphorsulfonic
acid salt in methyl ethyl ketone
Cis/trans-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin (2000 mg)
camphorsulfonic acid salt containing 94.6% of the cis-isomer in
methyl ethyl ketone (10 mL) was heated to 70-75.degree. C. for 15
minutes. The heating was stopped and the reaction mixture stirred
for 2 hours at room temperature. The precipitate was filtered and
the cake washed with methyl ethyl ketone to give a 98.9:1.1
cis/trans-mixture of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidin
camphorsulfonic acid salt (1800 mg).
Example X
Pulping of the cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin
camphorsulfonic acid salt in toluene
Cis/trans-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin (5 g)
camphorsulfonic acid salt containing 93.9% of the cis-isomer in
toluene (50 mL) was stirred between 20 to 25.degree. C. for 24
hours. The solid was filtered and the cake washed with toluene (10
mL) two times. This gave a 95.2:4.8 cis/trans mixture of
2-methylspiro(1,3-oxathiolane-5,3')quiniclidin camphorsulfonic acid
salt (4.8 g).
Example XI
Pulping of the cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin
camphorsulfonic acid salt in toluene/methanol
Cis/trans-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin (10 g)
camphorsulfonic acid salt containing 93.9% of the cis-isomer in
toluene (50 mL) and methanol (0.743 g) and was stirred between 20
to 25.degree. C. for 24 hours. The solid was filtered and the cake
washed with toluene (10 mL) two times. This gave a
cis/trans-mixture of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidin
camphorsulfonic acid salt (9.1 g, 98.42% cis-isomer). The solid was
stirred in toluene (50 mL) and methanol (0.743 g) between 20 to
25.degree. C. for 24 hours. This gave a 99.66:0.34
cis/trans-mixture of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidin
camphorsulfonic acid salt (7.7 g).
Example XII
Preparation of the
cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin hydrochloric
acid salt
To a solution of cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin
camphorsulfonic acid salt (1.6 g, 3.71 mmol) in water (30 mL) was
added 20 mL of a solution of sodium carbonate to pH=10 at
0-5.degree. C. The aqueous layer was extracted with heptane
(3.times.50 mL). The combined organic layers were dried over sodium
sulphate, filtered and evaporated to yield 0.65 g of
cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin free base as an
oil. This material was dissolved in diethyl ether (10 mL), and
hydrochloric acid in iso-propanol (20% solution; 0.8 mL; 1.4
equiv.) was added. The mixture was stirred at room temperature for
4 hours. The precipitate was filtered and the cake washed with
diethyl ether to give
cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin hydrochloric
acid salt (900 mg, 2.9 mmol, 78% yield). This material contained 91
ppm toluene.
Example XIII
Preparation of the
cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin hydrochloric
acid salt: HCl gas in MTBE and HCl/MTBE solution
To a cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidin
camphorsulfonic acid salt (9.9 g, 23.0 mmol) in water (29 mL) was
added 2.2 g of 50% sodium hydroxide solution (pH=12) at 0-5.degree.
C. The solution was stirred for 15 minutes and extracted with
methyl tert-butyl ether (3.times.60 mL). The combined organic
phases were dried over sodium sulphate and filtered through
Celite.RTM.. The solution was cooled to 0-5.degree. C. and 11.05 g
of 8% HCl in methyl tert-butyl ether was added dropwise. The
precipitate was filtered and washed with methyl tert-butyl ether
(3.times.20 mL). The cake was dried under vacuum at room
temperature to give 5.3 g (22.6 mmol, 98% yield) of Cevimeline
hydrochloride. This material contained 17 ppm toluene. .sup.1H NMR
(400 MHz, CDCl.sub.3, cis-isomer): .delta.=5.19 (q, J=5.6 Hz, 1H);
3.46 (dd, J=2.0 Hz, J=13.7 Hz, 1H); 3.31 (d, J=11.2 Hz, 1H);
3.27-3.15 (m, 6H); 2.27-1.47 (m, 1H); 2.01-1.92 (m, 1H); 1.90-1.82
(m, 2H); 1.77-1.69 (m, 1H); 1.50 (d, J=5.9 Hz, 3H).
PXRD diffractograms were collected on a PANalytical X'Pert Pro MPD
diffractometer, using CuK.quadrature. radiation, and an X'Celerator
detector (real time multiple strip technology). The generator power
settings used were 45 kV and 40 mA. Diffractograms were collected
with a step size of 0.017.degree. 2.theta. and a step size of 11
seconds. Samples were prepared by the back loading technique.
PXRD (peak position +/-0.2.degree. 2.theta.; peaks listed are at
>5% relative intensity): 6.2, 12.4, 14.8, 15.2, 16.0, 16.2,
20.2, 21.6, 22.8, 23.5, 24.1, 24.8, 25.3, 29.2, 31.2, 33.7, 34.9,
37.5, 39.6
Furthermore, as many changes can be made to the invention without
departing from the scope of the invention, it is intended that all
material contained herein be interpreted as illustrative of the
invention and not in a limiting sense.
* * * * *